Drug-Polymer Coated Stent

ABSTRACT

The present invention provides a method and system for loading drug onto a stent. The method comprises positioning at least one polymer coated stent on a mandrel, positioning a drug infused sheath onto the stent and diffusing drug from the sheath into the polymer coating of the stent. The system includes a drug coated mandrel and sheath positioned adjacent to and in contact with a polymer coated stent.

FIELD OF THE INVENTION

This invention relates generally to biomedical stents. Morespecifically, the invention relates to a drug-polymer coating disposedon an endovascular stent for in vivo, drug delivery, and methods ofcoating thereof.

BACKGROUND OF THE INVENTION

Endovascular stents have become increasingly important in medicalprocedures to restore the function of bodily lumens. With generally opentubular structures, the stents typically have apertured or lattice-likewalls of a metallic or polymeric base, and can be either balloonexpandable or self-expanding. A stent is typically deployed by mountingthe stent on a balloon portion of a balloon catheter, positioning thestent in a body lumen, and expanding the stent by inflating the balloon.The balloon is then deflated and removed, leaving the stent in place.Stents help reduce the probability and degree of vessel blockage fromrestenosis.

An increasing number of stents for treating vascular conditions arebeing coated with protective materials and bioactive drugs. A variety ofstent coatings and compositions have been proposed to provide localizedtherapeutic pharmacological agents and treatment of a vessel at the sitebeing supported by the stent. Stent coatings with various families ofdrug polymer chemistries have been used to increase the effectiveness ofstenting procedures and to control drug-elution properties. For example,polymeric coatings can be made from polyurethane, polyester, polylacticacid, polyamino acid, polyorthoester, and polyphosphate ester. Examplesof drug or bioactive agents include antirestonotic and anti-inflammatorycompounds.

Medical research indicates a greater effectiveness of vascular stentswhen stents are coated with pharmaceutical drugs that help prevent ortreat medical conditions such as restenosis and thrombosis. These drugsmay be released from a coating while in the body, delivering theirpatent effects at the site where they are most needed. The localizedlevels of the medications can be elevated, and are therefore potentiallymore effective than orally or intravenously delivered drugs.Furthermore, drugs released from tailored stent coatings can havecontrolled, timed-release qualities, eluting their bioactive agents overhours, weeks or even months. Stent coatings typically have a drug oractive agent, which has been dissolved or dispersed throughout thepolymeric material and physically constrained within the polymer. Thesustained release of drugs generally relies upon either degradation ofthe polymer or diffusion through the polymer to control the elution ofthe compounds.

Stents can be coated with a polymer or combination of a polymer and apharmaceutical agent or drug by application techniques such as dipping,spraying, painting, and brushing. In many of the current medical deviceor stent coating methods, a composition of a drug and a polymer in asolvent is applied to a device to form a substantially uniform layer ofdrug and polymer. The concentration of the pharmaceutical agent or drugapplied to the stent varies depending on the pharmaceutical agent ordrug and the intended use of the pharmaceutical agent or drug.Generally, the dose of pharmaceutical agent or drug coated on a stentranges from nanograms to milligrams. A problem arises when trying tocoat stents with lower doses of pharmaceutical agent or drug.

A common solvent for the polymers and drugs employed is usuallyrequired, and techniques have been developed to micronize the drugs intosmall particles so that the drugs can be suspended in the polymersolution. Micronization can be time consuming, and may result in adegradation or loss of desired therapeutic properties of the drug. Amethod of using micronized drugs and layering a drug-coated stent usingpharmacological and polymeric agents is described by Guruwaiya et al. inU.S. Pat. No. 6,251,136 issued Jun. 26, 2001. A pharmacological agent isapplied to a stent in dry, micronized form over a sticky base coating. Amembrane-forming polymer, selected for its ability to allow thediffusion of the pharmacological agent therethrough, is applied over theentire stent. More specifically, a stent, typically a metal stent, has alayer of a sticky material applied to selected surfaces of the stent. Apharmacological agent is layered on the sticky material and a membraneforming a polymer coating is applied over the pharmacological agent. Themembrane is formed from a polymer that permits diffusion of thepharmacological agent over a predetermined time period.

A method of applying drug-release polymer coatings that uses solvents isdescribed in “Method of Applying Drug-Release Coatings”, Ding et al.,U.S. Pat. No. 5,980,972 issued Nov. 9, 1999. A polymer is dissolved inone solvent and a drug is dissolved or suspended in a similar ordifferent type of solvent. The solutions are applied either sequentiallyor simultaneously onto the devices by spraying or dipping to form asubstantially homogenous composite layer of the polymer and thebiologically active material.

Many of the drug-coated stents in recent years have been sprayed withrather than dipped in a drug-polymer solution. Spray coating, acurrently preferred method for coating stents, can result in asignificant amount of spray material lost during the process and whenexpensive drugs are used in these coatings, the use of spray coating maybe costly. Another drawback to spraying is that spraying deposits aninexact amount of therapeutic agent on the stent, potentially deliveringmore or less than desired. This is a problem where the therapy requiresa more controlled amount of drug be administered to the target site.This is also a problem where a very small concentration of therapeuticagent is to be applied to and eluted from the stent.

Dip coating was used with early stents and other medical-device designsthat were of relatively open construction fabricated from wires or fromribbons. Such coating methods were performed by manually dipping thestent in a liquid, and then removing the stent and drying it. Thedipping process requires care to avoid excess liquid on the stentframework or inconsistent drying of the liquid, otherwise the aperturescan become blocked unnecessarily. Applying a thick coating tends toexacerbate webbing and bridging problems, and increasing the solidscontent of the coating solution also increases webbing and bridgingbetween the struts. Any coating method needs to avoid webbing, as wellas control the weight and thickness of a coating.

Newer stents that are of less open construction, such ascatheter-deployed, self-expanding stents are more difficult to coatevenly using a dipping method. Nevertheless, one advantage of dipcoating is the ability to process a greater number of stents in a moreefficient manufacturing process.

Dipping as a method of coating medical devices is described in U.S.Patent Application No. 20020082679 published Jun. 27, 2002 entitled“Delivery or Therapeutic Capable Agents” to Sirhan and Yan. Barry et al.describe another method of dip coating a stent with a polymercomposition that can be used for delivering substantiallywater-insoluble drugs in “Loading and Release of Water-insoluble Drugs”,U.S. Pat. No. 6,306,166 issued Oct. 23, 2001.

Multiple dips can be used to build up the weight and thickness of thecoating, but each subsequent dip may affect the coating alreadydeposited. A coating can re-dissolve in a second coating solution,causing some loss of the first layer of coating. Also, applications ofmultiple dip coats from low concentration solutions can have the effectof reaching a limiting loading level as equilibrium is reached betweenthe solution concentration and the amount of coating with or without apharmaceutical agent. One such method that applies a plurality ofrelatively thin coatings on an open-lattice stent is disclosed in “DrugRelease Stent Coating”, Ding et al., U.S. Pat. No. 6,358,556 issued Mar.19, 2002. The stents are coated by dipping or, preferably, spraying thestent with a solvent mixture of uncured polymeric silicone material witha cross-linker and a finely divided biologically active species.

Accordingly, what is needed is a method for coating medical devices suchas stents with drug-polymer coating with more accuracy than currentmethods of coating and that overcomes the deficiencies and limitationsdescribed above.

SUMMARY OF THE INVENTION

One aspect of the invention provides a method of loading drug onto astent. The method comprises positioning at least one polymer coatedstent on a mandrel, positioning a drug infused sheath onto the stent anddiffusing drug from the sheath into the polymer coating of the stent.

Another aspect of the invention provides a system for loading drug ontoa stent. The system comprises a polymer coated stent and a stent holdingmember. The stent holding member is sized to receive the polymer coatedstent. The system further includes a drug-coated sheath sized to fitaround the stent and mandrel during diffusion of the drug into thepolymer coating on the stent.

Another aspect of the invention is a method of treating a vascularcondition. The method includes the steps of inserting a drug-polymercoated stent within a vessel of a body, the drug-polymer coated stentincluding a drug-polymer coating having at least one therapeutic agentand eluting at least one therapeutic agent from the laminateddrug-polymer coating into the body.

The present invention is illustrated by the accompanying drawings ofvarious embodiments and the detailed description given below. Thedrawings should not be taken to limit the invention to the specificembodiments, but are for explanation and understanding. The detaileddescription and drawings are merely illustrative of the invention ratherthan limiting, the scope of the invention being defined by the appendedclaims and equivalents thereof. The foregoing aspects and otherattendant advantages of the present invention will become more readilyappreciated by the detailed description taken in conjunction with theaccompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of a system for treating a vascular conditionincluding a drug-polymer coated stent coupled to a catheter, inaccordance with one embodiment of the current invention;

FIGS. 2 a and 2 b illustrate one embodiment of a system for applying atherapeutic agent to a polymer-coated stent, in accordance with oneembodiment of the current invention;

FIGS. 3 a and 3 b illustrate another embodiment of a system for applyinga therapeutic agent to a polymer-coated stent, in accordance with oneembodiment of the current invention;

FIG. 4 is a flow diagram of a method of applying a therapeutic agent ona polymer coated stent, in accordance with one embodiment of the currentinvention; and

FIG. 5 is a flow diagram of a method for treating a vascular condition,in accordance with one embodiment of the current invention.

DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS

FIG. 1 shows an illustration of a system for treating a vascularcondition, comprising a drug-polymer coated stent coupled to a catheter,in accordance with one embodiment of the present invention at 100.Coated stent with catheter 100 includes a drug-polymer coated stent 120coupled to a delivery catheter 110. Drug-polymer coated stent 120includes a stent framework 130 and a drug-polymer coating 140 disposedon stent framework 130. Drug-polymer coating 140 is applied to at leasta portion of the stent framework, such as an inner surface 132 of stentframework 130, an outer surface 134 of stent framework 130, or bothinner surface 132 and outer surface 134 of stent framework 130. In otherembodiments, portions of the sent may be coated with a drug-polymercoating, leaving some of the stent uncoated. For example, only the endsof the stent may be coated or only the middle of the stent may becoated, leaving the ends uncoated. Drug-polymer coating 140 comprises adrug-polymer and at least one therapeutic agent.

Stent framework 130 comprises a metallic base or a polymeric base, suchas stainless steel, nitinol, tantalum, MP35N alloy, platinum, titanium,a chromium-based alloy, a suitable biocompatible alloy, a suitablebiocompatible material, a biocompatible polymer, or a combinationthereof. The polymeric base material may comprise any suitable polymerfor biomedical stent applications, as is known in the art.

Insertion of coated stent 120 into a vessel of a body helps treat, forexample, heart disease, various cardiovascular ailments, and othervascular conditions. Catheter-deployed coated stent 120 typically isused to treat one or more blockages, occlusions, stenoses or diseasedregions in the coronary artery, femoral artery, peripheral arteries, andother arteries in the body. Treatment of vascular conditions may includethe prevention or correction of various ailments and deficienciesassociated with the cardiovascular system, the cerebrovascular system,urinogenital systems, biliary conduits, abdominal passageways and otherbiological vessels within the body.

An exemplary drug-polymer coating 140 includes or encapsulates one ormore therapeutic agents. Drug-polymer coating 140 may comprise one ormore therapeutic agents dispersed within or encased by drug-polymerlayers on coated stent 120, which are eluted from coated stent 120 withcontrolled time delivery after the deployment of coated stent 120 intothe body. A therapeutic agent is capable of producing a beneficialeffect against one or more conditions including coronary restenosis,cardiovascular restenosis, angiographic restenosis, arteriosclerosis,hyperplasia, and other diseases or conditions. For example, thetherapeutic agent can be selected to inhibit or prevent vascularrestenosis, a condition corresponding to a narrowing or constriction ofthe diameter of the bodily lumen where the stent is placed. Drug-polymercoating 140 may comprise, for example, an antirestenotic drug such asrapamycin, a rapamycin analogue, or a rapamycin derivative to prevent orreduce the recurrence or narrowing and blockage of the bodily vessel.Drug-polymer coating 140 may comprise an anti-cancer drug such ascamptothecin or other topoisomerase inhibitors, an antisense agent, anantineoplastic agent, an antiproliferative agent, an antithrombogenicagent, an anticoagulant, an antiplatelet agent, an antibiotic, ananti-inflammatory agent, a steroid, a gene therapy agent, an organicdrug, a pharmaceutical compound, a recombinant DNA product, arecombinant RNA product, a collagen, a collagenic derivative, a protein,a protein analog, a saccharide, a saccharide derivative, a bioactiveagent, a pharmaceutical drug, a therapeutic substance, or a combinationthereof.

The elution rates of the therapeutic agents and total drug eluted intothe body and the tissue bed surrounding the stent framework are based onthe thickness of drug-polymer coating 140, the constituency ofdrug-polymer coating 140, the nature and concentration of thetherapeutic agents, the thickness and composition of any cap coat, andother factors. Drug-polymer coating 140 may include and elute multipletherapeutic agents to achieve the desired therapeutic effect.Drug-polymer coating 140 can be tailored to control the elution of oneor more therapeutic agents, primarily by diffusion processes. In somecases, a portion of drug-polymer coating 140 dissolves and is absorbedinto the body, releasing therapeutic agents from within the coating asthe therapeutic agents are exposed to the surrounding tissue bed orbodily fluids flowing through the coated stent. In other cases,drug-polymer coating 140 erodes from coated stent 120 to release thetherapeutic compounds, the residual polymer being expelled by the body.

Incorporation of a drug or other therapeutic agent into drug-polymercoating 140 allows, for example, the rapid delivery of apharmacologically active drug or bioactive agent within twenty-fourhours following the deployment of a stent, with a slower, steadydelivery of a second bioactive agent over the next three to six months.For example, a first therapeutic agent may comprise an antirestenoticdrug such as rapamycin, a rapamycin analogue, or a rapamycin derivative.The second therapeutic agent may comprise, for example, an anti-cancerdrug such as camptothecin or other topoisomerase inhibitors.

The amount of the therapeutic agent applied to the stent through thedrug-polymer coating may vary depending on the characteristics of theparticular agent or combination of agents, the length of time the stentis in place and other factors well known to those with skill in the art.In one embodiment, the drug or therapeutic agent is coated to achieve atotal amount loaded on the stent to be between about 1 μg to about 10μg. In another embodiment, the amount loaded onto the stent is betweenabout 10 μg to about 1000 μg. Those with skill in the art will recognizethat the method of loading the drug or therapeutic agent disclosed hereallows for precise control of the amount loaded as well as allows forthe loading of amounts below that allowed by current methods ofapplication such as, for example, dipping, spraying and brushing.

Catheter 110 of an exemplary embodiment of the present inventionincludes a balloon 112 that expands and deploys the stent within avessel of the body. After positioning coated stent 120 within the vesselwith the assistance of a guide wire traversing through a guidewire lumen114 inside catheter 110, balloon 112 is inflated by pressurizing a fluidsuch as a contrast fluid that fills a tube inside catheter 110 andballoon 112. Coated stent 120 is expanded until a desired diameter isreached, and then the fluid is depressurized or pumped out, separatingballoon 112 from coated stent 120 and leaving coated stent 120 deployedin the vessel of the body. Alternatively, catheter 110 may include asheath that retracts to allow expansion of a self-expanding version ofcoated stent 120.

FIGS. 2 a and 2 b illustrate a system for applying a drug-polymercoating to a stent, in accordance with one embodiment of the presentinvention at 200. Stent coating system 200 provides a system foruniformly applying a therapeutic agent to both the inside and outsidediameter of the stent. Coating system 200 includes a polymer-coatedstent 220, stent holding member (mandrel) 230 and drug delivery sheath250. Polymer coated stent 220 includes a stent framework 222 with apolymer coating 224 disposed on stent framework 222. Polymer coating 224may be uniformly distributed around stent framework 222 thereby coatingthe entirety of stent 220. Polymer coating 224 may be any one orcombination of polymers well known to those with skill in the art.Polymer coating 224 may be, for example, poly(ethylene-vinyl acetate)(PEVA), polyurethane, polycaprolactone, phosphoryl choline or a blendedpolymer of polyurethane and polycaprolactone.

Stent framework 222 comprises a metallic base or a polymeric base, suchas stainless steel, nitinol, tantalum, MP35N alloy, platinum, titanium,a chromium-based alloy, a suitable biocompatible alloy, a suitablebiocompatible material, a biocompatible polymer, or a combinationthereof. The polymeric base material may comprise any suitable polymerfor biomedical stent applications, as is known in the art.

Mandrel 230 is of a size and shape suitable to support a stent forcoating. The stent may be coated in the fully deployed state, the rolleddown state or a partially open state. Stent 220 is disposed around themandrel adjacent to the outside surface 235 of mandrel 230. The outsidesurface 235 of mandrel 230 includes a drug-polymer coating 240.Drug-polymer coating 240 may comprise a drug or other therapeutic agentof the type described above for FIG. 1 or any other suitable agent wellknown in the art. Drug-polymer coating 240 may be applied to mandrel 230by dipping, spraying, brushing or any other means known in the art.

Drug delivery sheath 250 includes a drug-polymer coating 260 applied tosheath surface 255. Drug delivery sheath 250 is composed of a flexiblematerial suitable for wrapping around the stent mandrel assembly 210. Inone embodiment, drug delivery sheath 250 is a polymer. The polymer maybe, for example, poly(ethylene-vinyl acetate) (PEVA), polyurethane,polycaprolactone, phosphoryl choline, a blended polymer of polyurethaneand polycaprolactone or any other polymer well known to those with skillin the art.

Drug-polymer coating 260 may comprise a drug or other therapeutic agentof the type described above for FIG. 1 or any other suitable agent wellknown in the art. Drug-polymer coating 260 may include the same drug andpolymer combination as that of drug-polymer coating 240 coated onmandrel 230 or it may be a different drug or therapeutic agent.Drug-polymer coating 260 may be applied to drug delivery sheath 250 bydipping, spraying, brushing, or any other means known in the art.Alternatively, the drug polymer coating may be applied by the methodaccording to the present invention and described in more detail below.

In operation, drug delivery sheath 250 is wrapped around stent mandrelassembly 210 so that the drug-coated surface 255 of sheath 250 contactsthe polymer coated stent framework 222. In this position, the drug ortherapeutic agent of drug-polymer coating 240 and drug-polymer coating260 will be diffused (transferred) to the polymer-coated stent. Thediffusion of the drug or therapeutic agent will continue until a stateof equilibrium is reached or until the stent is removed from contactwith the mandrel and sheath. FIG. 2 b is a cross section of system 200taken along line A-A after the sheath 250 is wrapped around stentmandrel assembly 210.

The time that it takes to reach equilibrium varies depending on factorssuch as concentration of the drug or therapeutic agent on the sheath andmandrel, thickness of the polymer coating on the stent, molecular weightof the drug or therapeutic agent, and size of the molecule of the drugor therapeutic agent. The rate at which equilibrium is reached also maydepend on the specific characteristics of the polymer coating.

The rate of diffusion of the drug or therapeutic agent from thedrug-polymer coatings of the mandrel and the sheath to the polymercoating on the stent may be enhanced by increasing the temperature atwhich the sheath covered stent is placed. The sheath-covered stent maybe place in an oven at temperatures ranging from about room temperatureto a temperature below that at which the drug or therapeutic agentdegrades. Those with skill in the art will recognize that the uppertemperature limit depends on the specific drug or therapeutic agent.

The rate of diffusion may also be affected by increasing the atmosphericpressure to which the sheath-covered stent is exposed. In oneembodiment, the sheath-covered stent may be placed in a pressure chamberand the pressure adjusted to above atmospheric pressure. The pressuremay be increased, for example from about 0 atmospheres to about 150atmospheres.

The rate of diffusion may also be affected by placing the sheath-coveredstent in a solvent. The solvent may aid in the diffusion by providing amore suitable environment for the drug or therapeutic agent to migratebetween the sheath mandrel and the polymer-coated stent. The solvent maybe organic or inorganic. Those with skill in the art will recognize thatthe choice of solvent will depend on the characteristics of the drug ortherapeutic agent to be coated.

Once equilibrium between the drug-polymer coated stent and the sheathand mandrel has been reached or a specific time has elapsed, the sheathmay be removed from the stent mandrel assembly and the stent removedfrom the mandrel.

A cap coating may be applied to the drug-polymer coated stent before orafter it is removed from the mandrel 230. The cap coating is applied byusing, for example, any suitable application technique such as dipping,spraying, brushing or painting. The cap coating provides a level ofscratch and abrasion resistance during the handling of the coated stent,and can serve as a diffusion barrier that provides additional controlover the elution of therapeutic agents from the drug-polymer coatingafter deployment of the stent within the body. The cap coating may beformed from polymers such as polycaprolactone, polyglycolide,poly(lactide-co-glycolide), a silicone-urethane copolymer, apolyurethane, or poly(ethylene-vinyl acetate). Multiple cap coats may beapplied to achieve a thicker cap coating.

In another embodiment of system 200, the mandrel does not include adrug-polymer coating. This embodiment may be used for applying drug ortherapeutic agent to only the outer diameter of the polymer coatedstent.

Those with skill in the art will appreciate that the drug may be appliedin such a manner as to have a higher concentration of the drug in theouter polymer layer of the coated stent and a lower concentration in thepolymer layer closest to the stent framework. This may be accomplishedas a factor of time and by not allowing equilibrium to be achieved.Applying the drug to the stent in this manner preferentially loads thedrug at the outer diameter of the stent where it is most useful. A stenthaving such a coating may be useful for situations where a higher doseof drug or therapeutic agent is initially required and a lower doesdesired over time.

Those with skill in the art will also recognize that system 200 may bedesigned to coat more than one stent at a time. For example, the mandrel230 may be appropriately sized to accommodate two or more stents 220with a correspondingly sized sheath 250.

FIGS. 3 a and 3 b illustrate a system for applying a drug-polymercoating to a stent, in accordance with another embodiment of the presentinvention at 300. Stent coating system 300 provides a system foruniformly applying a therapeutic agent to both the inside and outsidediameter of the stent. Coating system 300 includes a polymer-coatedstent 320, stent holding member (mandrel) 330 and drug delivery sheath350. Polymer coated stent 320 includes a stent framework 322 with apolymer coating 324 disposed on stent framework 322. Polymer coating 324may be uniformly distributed around stent framework 322 thereby coatingthe entirety of stent 320. Polymer coating 324 may be any one orcombination of polymers well known to those with skill in the art.Polymer coating 324 may be, for example, poly(ethylene-vinyl acetate)(PEVA), polyurethane, polycaprolactone, phosphoryl choline or a blendedpolymer of polyurethane and polycaprolactone.

Stent framework 322 comprises a metallic base or a polymeric base, suchas stainless steel, nitinol, tantalum, MP35N alloy, platinum, titanium,a chromium-based alloy, a suitable biocompatible alloy, a suitablebiocompatible material, a biocompatible polymer, or a combinationthereof. The polymeric base material may comprise any suitable polymerfor biomedical stent applications, as is known in the art.

Those with skill in the art will recognize that stents composed of apolymer or a combination of polymers may not require that a polymercoating be applied prior to application of the drug or therapeutic agentto the stent.

Mandrel 330 is of a size and shape suitable to support a stent forcoating. The stent may be coated in the fully deployed state, the rolleddown state or a partially open state. Stent 320 is disposed around themandrel adjacent to the outside surface 335 of mandrel 330. The outsidesurface 335 of mandrel 330 includes a drug-polymer coating 340.Drug-polymer coating 340 may comprise a drug or other therapeutic agentof the type described above for FIG. 1 or any other suitable agent wellknown in the art. Drug-polymer coating 340 may be applied to mandrel 330by dipping, spraying, brushing or any other means known in the art.

Drug delivery sheath 350 includes a drug-polymer coating 360 applied toinner sheath surface 355. Drug delivery sheath 350 is composed of aflexible material suitable for placing around the stent mandrel assembly310. In one embodiment, drug delivery sheath 350 is a polymer. Thepolymer may be, for example, poly(ethylene-vinyl acetate) (PEVA),polyurethane, polycaprolactone, phosphoryl choline, a blended polymer ofpolyurethane and polycaprolactone or any other polymer well known tothose with skill in the art.

Drug-polymer coating 360 may comprise a drug or other therapeutic agentof the type described above for FIG. 1 or any other suitable agent wellknown in the art. Drug-polymer coating 360 may include the same drug andpolymer combination as that of drug-polymer coating 340 coated onmandrel 330 or it may be a different drug or therapeutic agent.Drug-polymer coating 360 may be applied to the inside surface 355 drugdelivery sheath 350 by dipping, spraying, brushing or any other meansknown in the art.

In operation, drug delivery sheath 350 is placed around stent mandrelassembly 310 so that the drug-coated surface 355 of sheath 350 contactsthe polymer coated stent framework 322. The sheath may be composed ofmaterial that offers a degree of elasticity so that the sheath can beplaced around and in contact with stent-mandrel assembly 310. In thisposition, the drug or therapeutic agent of drug-polymer coating 340 anddrug-polymer coating 360 will be transferred (diffused) to thepolymer-coated stent. The diffusion of the drug or therapeutic agentwill continue until a state of equilibrium is reached or until the stentis removed from contact with the mandrel and sheath. FIG. 3 b is a crosssection of system 300 taken along line B-B after the sheath 350 isplaced around stent mandrel assembly 310.

The time that it takes to reach equilibrium varies depending an factorssuch as concentration of the drug or therapeutic agent on the sheath andmandrel, thickness of the polymer coating on the stent, molecular weightof the drug or therapeutic agent, and size of the molecule of the drugor therapeutic agent. The rate at which equilibrium is reached also maydepend on the specific characteristics of the polymer coating.

The rate of diffusion of the drug or therapeutic agent from thedrug-polymer coatings of the mandrel and the sheath to the polymercoating on the stent may be enhanced by increasing the temperature atwhich the sheath covered stent is placed. The sheath-covered stent maybe placed in an oven at temperatures ranging from about room temperatureto a temperature below that at which the drug or therapeutic agentdegrades. Generally, the temperature range at which the sheath-coveredstent may be placed is between about 20 degrees Celsius to about 100degrees Celsius. Those with skill in the art will recognize that theupper temperature limit depends on the specific drug or therapeuticagent.

The rate of diffusion may also be affected by increasing the atmosphericpressure to which the sheath-covered stent is exposed. In oneembodiment, the sheath covered stent may be placed in a pressure chamberand the pressure adjusted to above atmospheric pressure. The pressuremay be increased, for example from about 0 atmospheres to about 150atmospheres.

The rate of diffusion may also be affected by placing the sheath-coveredstent in a solvent. The solvent may aid in the diffusion by providing amore suitable environment for the drug or therapeutic agent to migratebetween the sheath mandrel and the polymer-coated stent. The solvent maybe organic or inorganic. Those with skill in the art will recognize thatthe choice of solvent will depend on the characteristics of the drug ortherapeutic agent to be coated.

Once equilibrium between the drug-polymer coated stent 322 and thesheath and mandrel has been reached or a specific time has elapsed, thesheath 350 may be removed from the stent mandrel assembly and the stentremoved from the mandrel. The sheath may be removed by cutting thesheath from the stent-mandrel assembly or in any other way so as not todamage the drug-polymer coating on stent 322. In another embodiment, thesheath is pressurized in order to expand the sheath sufficiently to aidits removal from the stent-mandrel assembly.

A cap coating may be applied to the drug-polymer coated stent before orafter it is removed from the mandrel 330. The cap coating is applied byusing, for example, any suitable application technique such as dipping,spraying, brushing or painting. The cap coating provides a level ofscratch and abrasion resistance during the handling of the coated stent,and can serve as a diffusion barrier that provides additional controlover the elution of therapeutic agents from the drug-polymer coatingafter deployment of the stent within the body. The cap coating may beformed from polymers such as polycaprolactone, polyglycolide,poly(lactide-co-glycolide), a silicone-urethane copolymer, apolyurethane, or poly(ethylene-vinyl acetate). Multiple cap coats may beapplied to achieve a thicker cap coating.

In another embodiment of system 300, the mandrel does not include adrug-polymer coating. This embodiment may be used for applying drug ortherapeutic agent to only the outer diameter of the polymer coatedstent.

Those with skill in the art will appreciate that the drug may be appliedin such a manner as to have a higher concentration of the drug in theouter polymer layer of the coated stent and a lower concentration in thepolymer layer closest to the stent framework. This may be accomplishedas a factor of time and by not allowing equilibrium to be achieved. Astent having such a coating may be useful for situations where a higherdose of drug or therapeutic agent is initially required and a lower doesdesired over time.

Those with skill in the art will also recognize that system 300 may bedesigned to coat more than one stent at a time. For example, the mandrel330 may be appropriately sized to accommodate two or more stents 320with a correspondingly sized sheath 350.

In another embodiment, the drug coated mandrel is not used to supportthe stent. In this embodiment, a self expanding polymer coated stent isplaced within the sheath and allowed to expand to a point where thepolymer coating of the stent framework is adjacent to and in contactwith the drug-polymer coating on the inside surface of the drug deliverysheath. The stent is kept in an expanded state within the sheath untilthat time that equilibrium is reached or a predetermined amount of timehas elapsed.

FIG. 4 shows a flow diagram of a method of applying a drug-polymercoating on a stent, in accordance with one embodiment of the presentinvention at 400. Drug-polymer application method 400 includes varioussteps to form a drug-polymer coating on a stent framework.

A stent framework is cleaned, (Block 405). The stent framework may becleaned, for example, by inserting the stent framework into varioussolvents, degreasers and cleansers to remove any debris, residues, orunwanted materials from the surface of the stent framework. The stentframework is dried, and generally inspected at this point in theprocess.

After cleaning, a primer coating may be disposed on the stent framework,particularly to metallic stent frameworks such as stainless steel,assisting in the adhesion of the laminated drug-polymer coating to thestent framework. The primer coating may include, for example, theapplication of a suitable primer layer such as parylene, polyurethane,phenoxy, epoxy, polyimide, polysulfone, or pellathane. The primercoating may be applied to the stent framework by dipping, spraying,painting, brushing, or other suitable methods. The primer

coating is dried and cured or cross-linked as needed for eliminating orremoving any volatile components. Excess liquid may be blown off priorto drying the primer coating, which may be done at room temperature orelevated temperatures under a dry nitrogen or other suitable environmentincluding a vacuum environment.

A polymeric coating is applied onto at least a portion of the stentframework (Block 410). The polymeric coating may comprise, for example,a primer coating. The polymeric coating is applied using any suitablecoating technique such as dipping, spraying, painting, or brushing.Exemplary applied polymeric coatings comprise polymers such aspoly(vinyl alcohol), poly(ethylene-vinyl acetate), polyurethane,polycaprolactone, polyglycolide, poly(lactide-co-glycolide),poly(ethylene oxide), poly(vinyl pyrrolidone), silicone, an acrylicpolymer, an acrylic and acrylonitrile copolymer, a latex polymer, athermoplastic polymer, a thermoset polymer, a biostable polymer, abiodegradable polymer, a blended polymer, a copolymer, and combinationsthereof. Those with skill in the art will recognize that the polymericcoating may not be applied to stents composed of a polymeric base.

The dipped, sprayed or brushed stent framework is then dried (Block415). The coated stent framework may be dried, for example, bypositioning the coated stent framework in air and evaporating anysolvent from the applied polymeric coating. The polymeric coating isgenerally dried after application by evaporating the solvent at roomtemperature and under ambient conditions. A nitrogen environment orother controlled environment may also be used for drying. Alternatively,the polymeric coating can be dried by evaporating the majority of anysolvent at room temperature, and then further drying the coating in avacuum environment between, for example, a room temperature of about 20degrees centigrade and a temperature below that of the degradationtemperature of the drug or polymer, for example a temperature less than100 degrees Celsius. Drying in a vacuum environment helps to extract anypockets of solvent buried within the polymeric coating and to providethe desired level of crosslinking in the polymer.

A drug-polymeric coating is applied onto at least the drug deliverysheath (Block 420). The drug-polymer coating may also be applied to themandrel. The polymeric coating is applied using any suitable coatingtechnique such as dipping, spraying, painting, or brushing. Exemplaryapplied polymeric coatings comprise polymers such as poly(vinylalcohol), poly(ethylene-vinyl acetate), polyurethane, polycaprolactone,polyglycolide, poly(lactide-co-glycolide), poly(ethylene oxide),poly(vinyl pyrrolidone), silicone, an acrylic polymer, an acrylic andacrylonitrile copolymer, a latex polymer, a thermoplastic polymer, athermoset polymer, a biostable polymer, a biodegradable polymer, ablended polymer, a copolymer, and combinations thereof. One or moretherapeutic agents are added to and dispersed within the polymericcoating before its application onto the drug delivery sheath and/ormandrel. The therapeutic agents may be any one or more of thosediscussed above in relation to FIG. 1 or any other drug or therapeuticagent known in the art.

The polymer-coated stent is disposed on the drug-polymer coated mandrelso that the polymer coating on the inside diameter of the stentframework is adjacent and in contact with the drug-polymer coating ofthe mandrel (Block 425).

Next, the drug delivery sheath is placed on or wrapped around thestent-mandrel assembly so that the polymer coating on the outsidediameter of the stent framework is adjacent and in contact with thedrug-polymer coating of the drug delivery sheath (Block 430).

Once assembled, the drug or therapeutic agent coated on the sheath andor mandrel diffuses into the polymer layer coated on the stent framework(Block 435). As discussed above, the rate of diffusion may be affectedby increasing the ambient temperature at which the stent/sheath assemblyis placed or by increasing the pressure.

Once the drug or therapeutic agent has reached equilibrium or at aspecific predetermined time, the sheath and mandrel may be removed fromthe stent (Block 440).

The coated stent with the drug-polymer coating may be cross-linked asneeded (Block 445). Cross-linking may be done by providing additionaldrying cycles in air, or by heating the coated stent above a curingtemperature in an oven with a controlled ambient such as vacuum,nitrogen, or air.

A delivery catheter may be coupled to the coated stent (Block 450). Thedelivery catheter may include an inflatable balloon that is positionedbetween the coated stent and the catheter and used for deploying thecoated stent in the body. Alternatively, the delivery catheter mayinclude a sheath that retracts to deploy a self-expanding version of thecoated stent.

In one exemplary method, fully processed coated stents are reduced indiameter and placed into the distal end of the catheter to form aninterference fit, which secures the stent onto the catheter. Thecatheter with the stent may be placed in a catheter package andsterilized prior to shipping and storing.

The coated stent with the drug-polymer coating may be sterilized asneeded (Block 455). The stent is sterilized by any appropriate ormedically conventional means. Sterilization may employ, for example,gamma-ray irradiation, e-beam radiation, ethylene oxide gas, or hydrogenperoxide gas plasma sterilization techniques. The coated stent may bepackaged, shipped, and stored in a suitable package until it is used.

FIG. 5 shows a method of treating a vascular condition using adrug-polymer coated stent made in accordance with the present andreferred to generally as method 500. Method 500 begins by fabricating adrug-polymer coated stent including at least one drug-polymer layer(Block 510). The drug-polymer coated stent may be fabricated using themethod illustrated in FIG. 4.

When ready for deployment, the drug-polymer coated stent is insertedinto a vessel of the body and delivered to the target region within thepatient (Block 520). The stent is inserted typically in a controlledenvironment such as a catheter lab or hospital. The delivery catheter,which helps position the drug-polymer coated stent in a vessel of thebody, is typically inserted through a small incision of the leg and intothe femoral artery, and directed through the vascular system to adesired place in the vessel. Guide wires threaded through an inner lumenof the delivery catheter assist in positioning and orienting the coatedstent. The position of the coated stent may be monitored, for example,with a fluoroscopic imaging system or an x-ray viewing system.

The stent is then deployed (Block 530). The stent is deployed, forexample, by expanding the stent with a balloon or by extracting a sheaththat allows a self-expandable stent to enlarge after positioning thestent at a desired location within the body.

Once the coated stent is deployed, the therapeutic agents in thedrug-polymer coating are eluted. The elution rates of the therapeuticagents into the body and the tissue bed surrounding the stent frameworkare based on the polymers, thickness of the drug-polymer coating and anycap coating, and the distribution and concentration of the therapeuticagents contained therein, among other factors.

It is important to note that FIGS. 1-5 illustrate specific applicationsand embodiments of the present invention, and is not intended to limitthe scope of the present disclosure or claims to that which is presentedtherein. Upon reading the specification and reviewing the drawingshereof, it will become immediately obvious to those skilled in the artthat myriad other embodiments of the present invention are possible, andthat such embodiments are contemplated and fall within the scope of thepresently claimed invention.

While the embodiments of the invention disclosed herein are presentlyconsidered to be preferred, various changes and modifications can bemade without departing from the spirit and scope of the invention. Thescope of the invention is indicated in the appended claims, and allchanges that come within the meaning and range of equivalents areintended to be embraced therein.

1. A method loading drug onto a stent, the method comprising:positioning at least one polymer coated stent on a mandrel; positioninga drug infused sheath onto the stent; and diffusing drug from the sheathinto the polymer coating of the stent.
 2. The method of claim 1 whereinthe mandrel includes a drug-polymer coating having at least onetherapeutic agent on an outside surface of the mandrel and wherein themethod further comprises diffusing the therapeutic agent into thepolymer coating of the stent.
 3. The method of claim 1 wherein the druginfused sheath comprises a flat polymer sheet having a surface coatedwith at least one therapeutic agent.
 4. The method of claim 3 whereinpositioning a drug infused sheath onto the stent comprises wrapping theflat polymer sheet around the stent so that the coating having the atleast one therapeutic agent is adjacent to and in contact with thepolymer coated stent.
 5. The method of claim 1 wherein the drug infusedsheath comprises a polymeric cylinder having an inside surface, theinside surface including a drug-polymer coating applied thereon, thedrug polymer coating including at least one therapeutic agent.
 6. Themethod of claim 5 wherein positioning a drug infused sheath onto thestent comprises inserting the stent positioned on the mandrel into thepolymeric cylinder such that the inside surface is adjacent to and incontact with the polymer coated stent.
 7. The method of claim 1 furthercomprising placing the sheath covered stent into an oven, the oven at apredetermined temperature.
 8. The method of claim 7 wherein thepredetermined temperature is within the range of about 20 degreesCelsius to about 100 degrees Celsius
 9. The method of claim 1 furthercomprising placing the sheath covered stent into a pressurized chamberand increasing the pressure within the chamber, the pressure within therange of about 0 atmospheres to about 150 atmospheres.
 10. A system forloading drug onto a stent, the system comprising: a polymer coatedstent; and a stent holding member, wherein the holding member is sizedto receive the polymer coated stent.
 11. The system of claim 10 furthercomprising a drug infused sheath, the sheath sized to fit around thestent positioned on the stent holding member.
 12. The system of claim 10wherein the stent holding member includes a coating on an outsidesurface, the coating having at least one therapeutic agent containedtherein.
 13. The system of claim 11 wherein the drug infused sheathcomprises a flat polymer sheet having a surface coated with at least onetherapeutic agent.
 14. The system of claim 11 wherein the drug infusedsheath comprises a polymeric cylinder having an inside surface, theinside surface including a drug-polymer coating applied thereon, thedrug polymer coating including at least one therapeutic agent.
 15. Thesystem of claim 10 wherein the stent includes a stent framework.
 16. Thesystem of claim 15 wherein the stent framework comprises one of ametallic base or a polymeric base.
 17. The system of claim 16 whereinthe stent framework comprises a material selected from the groupconsisting of stainless steel, nitinol, tantalum, MP35N alloy, platinum,titanium, a chromium-based alloy, a suitable biocompatible alloy, asuitable biocompatible material, a biocompatible polymer, and acombination thereof.
 18. A method of treating a vascular condition,comprising: inserting a drug-polymer coated stent within a vessel of abody, the drug-polymer coated stent including a drug-polymer coatinghaving at least one therapeutic agent; and eluting at least onetherapeutic agent from the laminated drug-polymer coating into the body.19. The method of claim 18 wherein the drug-polymer coated stent isinserted into the vessel using a catheter.
 20. The method of claim 19wherein the catheter includes a balloon to expand the stent.
 21. Themethod of claim 19 wherein the catheter includes a sheath that retractsto allow expansion of the stent.
 22. A system for loading drug onto astent, the system comprising: a stent, the stent having a stentframework with a polymeric base; and a stent holding member, wherein theholding member is sized to receive the stent.
 23. The system of claim 22further comprising a drug infused sheath, the sheath sized to fit aroundthe stent positioned on the stent holding member.
 24. The system ofclaim 22 wherein the stent holding member includes a coating on anoutside surface, the coating having at least one therapeutic agentcontained therein.
 25. The system of claim 23 wherein the drug infusedsheath comprises a flat polymer sheet having a surface coated with atleast one therapeutic agent.
 26. The system of claim 23 wherein the druginfused sheath comprises a polymeric cylinder having an inside surface,the inside surface including a drug-polymer coating applied thereon, thedrug polymer coating including at least one therapeutic agent.
 27. Thesystem of claim 22 wherein the stent framework comprises a biocompatiblepolymer.
 28. A method for differentially loading drug on a polymercoated stent comprising: positioning at least one polymer coated stenton a mandrel; positioning a drug infused sheath onto the stent; andallowing the drug from the sheath to diffuse into the polymer coating ofthe stent for a period of time less than that required to establishequilibrium of the drug between the sheath and the polymer coating toestablish a drug concentration gradient characterized by a higherconcentration of drug in an outer polymer layer of said stent and alower concentration of drug in an inner polymer layer of said stent.